The diagnosis of neurodegenerative diseases is not easy. Thus, for Alzheimer's disease, according to the conventional “NINCDS-ADRDA” criteria (McKhann et al., (1984) Neurology 34: 939-944), a distinction is made between possible, probable and definite Alzheimer's disease, with it being possible to establish a diagnosis of definite Alzheimer's disease only post-mortem, after autopsy of the patient and neuropatho-logical examination of the brain demonstrating the existence of, on the one hand, senile plaques and, on the other hand, neurofibrillary degeneration.
The diagnosis of possible or probable Alzheimer's disease is based essentially on clinical criteria and neuropsychological tests which aim firstly to establish whether an individual is exhibiting a dementia syndrome, in general according to the DSM IV criteria (Diagnostic and Statistical Manual for Mental Disorders, 4th edition, American Psychiatric Association, 1994), and then to determine the etiology of the dementia. The criteria for dementia essentially comprise the combination of memory impairment and the impairment of other cognitive functions having an impact on socio-professional activities and leading to a decline compared with prior function. The diagnosis is reinforced by monitoring the patient's progress, which makes it possible to specify the causes of the dementia, in particular by ruling out other causes of cognitive decline. In this respect, brain imaging is an important element of the diagnosis through the evaluation of regional hippocampal atrophy, which can however be present in other diseases affecting the elderly, and through the exclusion of other causes of cognitive impairment, such as aftereffects of strokes.
However, it is generally considered that only approximately 85% of cases of probable Alzheimer's disease are confirmed post-mortem. The 15% of false positives generally result from other neurodegenerative diseases, such as frontotemporal dementia, including in particular dementia with Lewy bodies (Delacourte (1998) Annales de Biologie Cheque 56: 133-142). The current methodology for diagnosing Alzheimer's disease therefore lacks specificity. In addition, it appears that, between the triggering of the disease, defined by the appearance of the first cognitive impairment, and the first symptoms of dementia that may give rise to the establishing of a diagnosis of possible or probable Alzheimer's disease, there may be a period of more than 10 years (Amieva et al. (2008) Ann. Neural. 64: 479-480). The diagnosis of Alzheimer's disease is therefore currently established late, while the disease is at a very advanced stage. The current treatments envisioned for Alzheimer's disease would, however, in order to be effective, need to be carried out right from the beginning of the pathological process, for example while the individual to be treated still exhibits only mild cognitive impairment (MCI), which implies being able to diagnose the disease early.
In fact, supplementary examinations, such as the assaying of biochemical markers in the cerebrospinal fluid of patients, can be carried out in order to improve the diagnosis of Alzheimer's disease. Thus, it has in particular been shown that determining the levels, in the cerebrospinal fluid, of β-amyloid1-42 peptide (Aβ42) and the total level of tau (Tubulin Associated Unit) peptide, i.e. both in phosphorylated form and in nonphosphorylated form, makes it possible to diagnose Alzheimer's disease with a sensitivity of 92% and a specificity of 89% (Sunderland at al. (2003) JAMA 289: 2094-2103). Since then, a third marker has been added, in addition to Aβ42 and total tau (T-tau), namely phosphorylated tau (ptau), in particular phosphorylated on threonine 181 (ptau181). In addition, it has been possible to show that the combination of these three markers makes it possible to detect nascent Alzheimer's disease in individuals suffering from MCI with a sensitivity of 83% and a specificity of 72% (Matteson et al. (2009) JAMA 302: 385-393).
However, at the current time, these assays are not carried out routinely, partly because the gain that they enable in terms of reliability and earliness of the diagnosis of Alzheimer's disease is not sufficient to justify having recourse to said assays routinely.
The double-stranded RNA-dependent protein kinase (PKR) is a serine/threonine kinase of which the main target is eukaryotic translation initiation factor 2α (eIF2α). PKR exists in a form that is activated by phosphorylation of the threonine at position 446 and/or of the threonine at position 451. It has been possible to demonstrate high levels of activated PKR in particular in the brain of patients suffering from Alzheimer's disease, Huntington's disease and Creutzfeldt-Jakob disease, and also in the blood lymphocytes of patients suffering from Alzheimer's disease (for review see Hugon et al. (2009) Expert Rev. Neurother. 9: 1455-1457).